DDMODEL00000262: Sahota_2015_CPHPC_TMDD_model

  public model
Short description:
A mechanistic target mediated durg disposition model that predicts, with clinically acceptable precision,the exposure-response relationship for CPHPC, both in healthy individuals and in patients with systemic amyloidosis
Original code
  • Target Mediated Drug Disposition Model of CPHPC in Patients with Systemic Amyloidosis
  • T Sahota, A Berges, S Barton, L Cookson, S Zamuner, D Richards
  • CPT Pharmacometrics Syst. Pharmacol., 2/2015, Volume 4, Issue 2, pages: 116-126
  • Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, UK
  • The amyloid deposits that cause disease in systemic amyloidosis always contain the normal plasma protein, serum amyloid P (SAP) component. SAP is the target of a novel immunotherapy approach now being developed to eliminate amyloid deposits. The treatment is enabled by, and critically depends on, the use of the drug (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC, GSK2315698, Ro 63-8695), which depletes circulating SAP almost completely but leaves some SAP in amyloid deposits for specific recognition by subsequently administered therapeutic anti-SAP antibodies. Herein, we report a mechanistic model that predicts, with clinically acceptable precision, the exposure-response relationship for CPHPC, both in healthy individuals and in patients with systemic amyloidosis. The model covariates are gender, renal function, total amyloid load, and presence of hepatic amyloid, all of which are known at baseline. The model is being used to predict individualized dosing regimens in an ongoing, first-in-human study with anti-SAP antibodies.
Alienor Berges
Context of model development: Candidate Comparison, Selection, Human Dose Prediction;
Discrepancy between implemented model and original publication: None;
Model compliance with original publication: Yes;
Model implementation requiring submitter’s additional knowledge: No;
Modelling context description: The drug (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC, GSK2315698, Ro 63-8695) has been shown to deplete serum amyloid P (SAP) in plasma in studies in healthy volunteers (CPH113776) and patients with amyloidosis (CPH114527). In this modelling work, we have characterized the exposure-response relationship between CPHPC and plasma SAP concentration, both in healthy volunteers and in patients with systemic amyloidosis, and used the results to develop a robust pharmacokinetic-pharmacodynamic (PK-PD) model that predicts suitable dosing regimens for CPHPC in individual subjects.;
Modelling task in scope: simulation; estimation;
Nature of research: Early clinical development (Phases I and II);
Therapeutic/disease area: Oncology;
Annotations are correct.
This model is not certified.
  • Model owner: Alienor Berges
  • Submitted: Oct 25, 2017 12:45:23 PM
  • Last Modified: Oct 25, 2017 12:45:23 PM
  • Version: 3 public model Download this version
    • Submitted on: Oct 25, 2017 12:45:23 PM
    • Submitted by: Alienor Berges
    • With comment: Updated model annotations.